Ricin toxin is a biodefense concern, with documented attacks and ongoing attempts against civilian populations. Castor beans are ubiquitous and the toxin simple to purify. Aerosol exposure has the greatest potential for producing multiple casualties. Inhalation of ricin toxin induces acute pulmonary inflammation and can cause lethal respiratory failure. Survivors suffer long-term post-inflammatory lung damage. The long-term effects of aerosolized ricin can serve as a more general model of pulmonary pathogenesis, progressing from acute to chronic inflammation, and ultimately fibrosis and scarring. Currently there is no specific treatment for ricin toxicosis. Monoclonal antibodies (mAbs) to ricin offer significant post-exposure protection in experimental animals. We propose the use of passive antibody therapy to protect civilian populations. We favor passive mAb over active immunization, because we believe a ricin ?vaccine? would not be publicly accepted. Post-exposure treatment must protect when administered >12 hr post exposure; time required to diagnose the exposure, and to obtain and administer mAb. One of the objectives of this grant is to extend the therapeutic window of mAbs following ricin exposure. Here we propose to address the role of mAb structure (isotype, glycation) and route of delivery in defining the ability of mAbs to provide protection from both acute inflammation and long-term pathology. We will ask how mAb influences clearance of ricin, deposition of toxin-antitoxin immune complexes, localization of acute inflammation, and evolution of post-inflammatory pathology. We will ask if changing the Fc-region of the therapeutic mAb alters these processes. These studies aim to optimize mAb therapy for ricin exposure, but also use this as a well-characterized model to study the evolution of pulmonary pathology observed in many chronic pulmonary disorders, extending the import of these studies beyond biodefense. In this application we hypothesize that mAbs protect animals via multiple mechanisms, and that these mechanisms are influenced by the function of the Fc region. To address these hypotheses, we propose: Specific Aim 1: To characterize acute and chronic pulmonary tissue responses to ricin and mAb. Specific Aim 2: To determine which Fc functions are important for protection, clearance of antigen, and minimizing long-term pathological effects. Specific Aim 3: To determine the protection afforded by local vs systemic administration of mAb. These studies will produce better therapeutic agents for biodefense, and give a clearer understanding of the evolution of post-inflammatory pathology, and the role antibody plays in ameliorating this process.